This invention relates to new camptothecin analogues useful for the treatment of cancer, to intermediates useful for their synthesis, and to methods of preparing the analogues and intermediates.
Camptothecin (1) is a pentacyclic alkaloid possessing a fused quinoline in rings A and B, a pyrroline in ring C, an .alpha.-pyridone in ring D, and a six-membered lactone in ring E, and was first isolated from Camptotheca acuminata (Nyssaceae), a tree native to southern China (Wall, et al., J. Amer. Chem. Soc., 88, 3888-3890 (1966)). Promising antitumor and antileukemic activity and extreme rarity of the compound in nature (present in stem bark at abundances of about 0.01% by weight) have motivated extensive studies directed toward the total synthesis of camptothecin as well as the design of analogues intended to exhibit greater activity and lower toxicity than camptothecin itself. The results of these efforts have been comprehensively reviewed (C. R. Hutchinson, Tetrahedron, 37, 1047-1065 (1981); A. G. Schultz, Chemical Rev., 73, 385-405 (1973)).
Mechanistic studies of the biological action of camptothecin have pointed to the enzyme topoisomerase I as the main intracellular target of the compound. By binding to and stabilizing a covalent DNA-topoisomerase I complex in which a strand of DNA is broken (R. P. Hertzberg, et al., J. Med. Chem., 32, 715 (1989); W. D. Kingsbury, et al., J. Med. Chem., 34, 98 (1991)), it is believed, camptothecin damages DNA and strongly inhibits the synthesis of nucleic acids in cancer cells. A structure-activity correlation for camptothecin analogues has been established between the anti-cancer activity of an analogue and its ability to stabilize the DNA-topoisomerase I complex. Adding further weight to this belief, cell lines which are resistant to camptothecin have been determined to contain a mutated form of topoisomerase I (R. S. Gupta, et al., Cancer Res., 48, 6404 (1988)).
High toxicity and low solubility have diminished the clinical utility of camptothecin, stimulating a search for derivatives which transcend these limitations. Numerous analogues have been prepared by methods described in previous disclosures. None of these methods, however, offer a general approach for preparing camptothecin analogues with highly variable ring substitution patterns. For example, Miyasaka, et al. (U.S. Pat. No. 4,399,282), disclose camptothecin analogues substituted by an alkyl, aralkyl, alkoxycarbonyl, or alkoxyalkyl group exclusively in the 7-position, while J. C. Boehm, et al. (U.S. Pat. No. 5,004,758), disclose camptothecins substituted at positions 9 and 10, and Miyasaka, et al. (U.S. Pat. No. 4,473,692) provide compounds with certain groups located at positions 5, 7, and 10, but not otherwise. Because of the sparing solubility of camptothecin in many organic solvents, and because of the special characteristic of camptothecin that the aromatic rings are not sufficiently reactive, the usual electrophilic ring substitution reactions may not be performed on the parent structure, thereby making the preparation of many potentially valuable substitution patterns unobvious to one skilled in the chemical art. However, nitration has been effected by Chinese workers (P. Pei-chuang, et al., Hau Hsueh Hsueh Pao, 33, 71 (1975); Chem, Abstr., 84, 115629p (1975)) at the 12-position under forcing conditions (nitric acid/sulfuric acid) at the 9-position of a 10,11-methylenedioxycamptothecin (M. E. Wall, et al., U.S. Pat. No. 5,049,668), and at the 10-position by proceeding through a tetrahydrocamptothecin intermediate followed by subsequent re-oxidation (Miyasaka, et al., U.S. Pat. No. 4,473,692), thereby allowing access to a range of substitution but at the cost of starting from precious native camptothecin or its analogues.
Chemical modification of the A, B, and C ring is of greatest therapeutic interest based on previous structure-function studies. However, while most alterations in the D and E rings have depressed biological activity, certain modifications of these rings have been achieved without losing much activity, as disclosed in U.S. Pat. Nos. 3,894,029, 4,031,098, 4,914,205, and 4,943,579. The present invention uniquely allows simultaneous changes in substitution in all rings of camptothecin.
While several syntheses of camptothecin have been disclosed in prior art (for example, E. J. Corey, et al., J. Amer. Chem. Soc., 40, 2140 (1975); J. C. Bradley, et al., J. Org. Chem., 41, 699 (1976); G. Stork, et al., J. Amer. Chem. Soc., 93, 4074 (1971); E. Winterfeld, et al., Angew. Chem,, 84, 265 (1972)), the present approach offers the combined advantages of good preparative yield, a minimum number of reaction steps, and synthetic flexibility in the design of derivative analogues of camptothecin. Because of the intense anti-cancer activity of the parent structure and the possibility of obtaining a large variety of analogues, the present invention makes possible the development of a greater number of new target pharmaceuticals with more desirable chemical and clinical properties, including improved solubility, bioavailability, and anticancer activity. The present invention therefore represents a potentially important advance for cancer chemotherapy.